The ultimate goal of this project is to develop efficient and safe HIFU ablation technology for treating atrial fibrillation (AF) by the means of intraoperative or thoracoscopic operations. AF is the most common sustained cardiac arrhythmia, characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function. It increases a patient's risk of stroke and has a significant negative impact on quality of life. It is a significant public health problem incurring substantial health care costs. Current pharmacotherapy of AF is temporary, expensive, and has well-recognized limitations such as relatively low efficacy and often poorly tolerated systemic side effects. Ablation techniques have been exploited to replicate the cut-and-sew maze procedure by replacing the incisions with lines of ablation. While the choice of catheter or surgical ablation is best determined based on patient anatomy and history, energy surgical AF ablation has several advantages including the fact that the epicardial approach has a higher safety profile which is essential for AF ablation procedures, and that epicardial ablation can be performed in a much shorter period of time. Radiofrequency (RF), microwave, ultrasound, and cryo-therapy have been exploited for AF ablation, but current ablation technologies are not optimal for epicardial ablation, mainly due to their limited ability to create desired set of linear transmural lesions with minimum collateral damage. With its focus readily placed at depth to reach subsurface sites, high intensity focused ultrasound (HIFU) has the potential to overcome the limitations of current technologies to achieve better ablation outcome. However, major problems remain that have hindered the development of HIFU AF ablation. This project seeks to address these very problems in order to develop successful HIFU ablation therapy for AF. The specific aims of this project are: 1. To develop innovative imaging techniques for monitoring of HIFU ablation including high resolution ultrasound spectral imaging to assess tissue changes in HIFU exposures and a novel tomographic temperature imaging based on infrared (IR) thermography; 2. To characterize the electrophysiological, physical, and cellular changes in HIFU cardiac ablation. These mechanism-based comprehensive dose-response studies will investigate the spatiotemporal electrophysiological effects of HIFU ablation and correlate these effects with the temperature, lesion size, and histological changes in tissue using isolated Langendorff-perfused canine heart preparations and explanted human hearts in vitro. 3. To develop an image-guided HIFU array system for controlled epicardial ablation for effective and safe energy deposition for epicardial ablation on a beating heart. Tasks include: 1) to develop a HIFU array system capable of generating an electronically controlled versatile beam profile and variable focal depth; 2) to integrate imaging techniques for tissue temperature and lesion formation; 3) to demonstrate the ability of the prototype HIFU system for controlled epicardial ablation in vivo. Public Health Relevance Statement (provided by applicant): Atrial Fibrillation (AF) is the most common sustained cardiac arrhythmias. It is a significant public health problem, occurring in approximately 1% of the general population and in more than 10% of patients aged more than 80 years, incurring significant health care costs especially as the population ages. AF is characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function, leading to increased risk of stroke and reduction of quality of life for patients. The primary treatment for AF is pharmacotherapy, which is temporary, expensive, and has well-recognized limitations including relatively low efficacy and often poorly tolerated systemic side effects. The direct interventional therapy of AF by the surgical Cox-maze procedure remains the gold standard to treat and cure AF with over 90% efficacy. But the procedure has not gained wide spread application because the operation is technically challenging, requiring the creation of complex set of surgical incisions and reconstruction of the atria, and is associated with significant morbidity and mortality. Ablation therapy using high intensity focused ultrasound (HIFU) to create thermal lesions in the atriums could greatly simply surgical ablation procedure to treat AF. This project aims to develop an innovative, effective and safe ultrasound ablation therapy for treating AF.